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Drug Development in Asia – an Industry perspective. Stephen UdenPfizer Inc. ?. ?. ?. MHLW. Industry. Academia. Drug Development in Asia – an Industry perspective. Where are we today Where can we go in the future - PowerPoint PPT Presentation
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Drug Development in Asia – an Industry perspective
Stephen Uden Pfizer Inc.
Industry Academia MHLW
? ? ?
Drug Development in Asia – an Industry perspective
• Where are we today
• Where can we go in the future
– Path 1. Ever greater contribution to pharmaceutical and regulatory science
– Path 2. Simple bridging on the margins of drug research
Key accomplishments
• ICH established
• Adoption of GCP based on ICH
• Kikoh and PMDEC consultation process
• Time clock introduced
• MHLW vision
• Increasing interest in Clinical Research in Asia
• Scientific progress– Statistical methods
– Pharmacogenomics
Clinical trial activity – is it increasing?
• Clinical trials started to decline long before ICH was implemented
• Recently activity seems be increasing
0
500
1000
1500
2000
2500
1993 1994 1995 1996 1997 1998 1999 2000 2001
Company A
Company B
Company C
Company D
Clinical trial activity in Japan – patient recruitment experience from four companies
Year
Nu
mb
er o
f n
ew i
nfo
rmed
co
nse
nts
Clinical trial activity – is it increasing?
Company US EU Other Asia
A No No No
B Yes Yes Yes
C Yes Yes Yes
D Yes Yes No
E No No No
F Yes Yes Yes
G Yes Yes Yes
H No No Yes
Bridging out of Asia (Japan as an example)
PMDEC analysis Approval Time
0
100
200
300
400
500
600
700
800
1996 1997 1998 1999 2000
Total
MHLW/PMDEC
Sponsor
(Day)
(Median
)
(n=43) (36) (34) (44) (10)
Year of Submission
NCEs and LEsNCEs and LEsAs of June 2001As of June 2001
Increasing sophistication of scientific methodology
• Pharmacogenomics– Metabolic differences well understood– Some advances in pharmacodynamics
• Preclinical assessment– Metabolic pathways
• Statistical methodology– Sub-population analysis
Remaining Obstacles for Enhanced Drug Development
Remaining Obstacles for Enhanced Drug Development
• Ambiguity in drug development– Need for routine repetition of basic PK
Remaining Obstacles for Enhanced Drug Development
• Ambiguity in drug development– Need for routine repetition of basic PK
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
0 24 48 72 96Time post dose (h)
Pla
sma
conc
entr
atio
n (n
g/m
L) Japanese subject
Western subject
Japanese and Western young males (resident in Japan) Similar PK profiles in two populations
Large differences in cost between different areas discourage investment
0
1
2
3
4
5
6
Hong Kong Korea Japan US Turkey Argentina
Relative cost per patient for a large scale global outcomes study
Remaining Obstacles for Enhanced Drug Development
Unlike Phase II/III sites Japanese commercial Phase I units are
internationally competitive
0
0.5
1
1.5
2
EU - 1 EU - 2 EU - 3 EU - 4 J - 1 J - 2 J - 3 J - 4
Relative costs for a Phase I multiple dose study comparing Japanese and Caucasian normal volunteers
Re
lati
ve
co
st
Remaining Obstacles to Enhanced Drug Development
• Mind set– Unwillingness to collaborate– Beliefs prevailing over scientific evidence
and methodology– Sponsors unaware of changes
• Drug development expertise stagnating– Repetition of routine work inhibits
development of new methodology
Path 1 – the improvement trend continues
• Bridging evolves into making best use of data generated throughout the world
Path 1 – the improvement trend continues
Path 1 – the trend continues• Commitment to Asia being a centre of drug development
excellence• Regulators• Companies• Academics
• Costs brought under control in Japan• Investigators/Departments reimbursed directly• Institutional overhead costs controlled
• Adoption of robust scientific methodologies to cope with inevitable differences
• Statistical• Pharmacogenomics• Clinical technology
– Asian development centres identify critical issues for global development
– Opportunities for special population work in Asia– Sub populations prevalent in Asia– Metabolic groups– Patterns of medical practice
– End points validated in Asian patients
– Statistical methodologies to analyse sub-populations in the global database that are useful to Asian regulators and physicians
Discovery to first in man
– Pre-clinical assessment to determine likelihood of significant PK issues
– Application of statistical methodology to generate data relevant to Asians as part of global development programme
Clinical Pharmacology Programme
Integrated global PK programme Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US EU JapanSolid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point validation
Interaction study E
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Poor metaboliser study
PK in smokers
Interaction study C
Interaction study D
Special Study e.g. cognitive function
New formulation BE
Phase II/III population PK programme
Integrated global PK programme Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US EU JapanSolid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point validation
Interaction study E
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Poor metaboliser study
PK in smokers
Interaction study C
Interaction study D
Special Study e.g. cognitive function
New formulation BE
Phase II/III population PK programme
Statistical methodology applied to characterise PK in Japanese/Asians
Phase III
• Basic Efficacy accepted as relevant to all regions
• Integrated global strategy to determine how drug can best be used in individual patients– Best doses in sub-populations
• Sex• Co-morbid illness• Concomitant medication• Metabolic status
Integrated Phase III strategy - 1
US/Canada
Pivotal efficacy study IComparative efficacy
N = 500
EU/Europe
Pivotal efficacy study IIComparative efficacy
N = 500
Japan/Asia
Pivotal efficacy study IIIComparative efficacy
N = 500
Data combined to analyse for clinically important sub-populations•Sex•Co-morbid illness•Concomitant medication•Metabolic status
Integrated Phase III strategy - 2
Study 1Japan/other Asia/US/Canada/EU/Eastern Europe
Confirmation of efficacy
Study 2Japan/other Asia/US/Canada/EU/Eastern EuropeEfficacy comparative to different class of drug
Study 2Japan/other Asia/US/Canada/EU/Eastern Europe
Efficacy in special population
Regional specific issuesResolved through pre-Planned use of: • Pop PK• Sub Group analysis• Pharmacogenomics
Integrated Phase III strategy - 3
Global Outcomes study in Asia, Americas, Europe
Regional specific issuesResolved through pre-Planned use of: • Pop PK• Sub Group analysis• Pharmacogenomics
Sub study A Sub study B Sub study C
Clinical trial activity – definitely increases?
• Return to 1993 level?
• Studies more complex and “value added”?
A successful simultaneous development bridging strategy with
simultaneous filing/approval
Year 1 Year 2 Year 3 Year 4 Year 5
Phase I and II Global Development
Asia
= Phase III start
US or EU
= Filing
A successful simultaneous development bridging strategy with
simultaneous filing/approval
Year 1 Year 2 Year 3 Year 4 Year 5
Phase I and II Global Development
Asia
= Phase III start
US or EU
= Filing
Path 2 – stagnation or reversal
• Bridging degenerates into multiple repetitive studies throughout Asia
• Japan destined to perform basic PK studies and routine (Phase II) Bridging studies
Path 2 – stagnation or reversal
• Nationality seen as more important than physiological or pathological status
• Only nationally produced data is seen as relevant
• Costs continue to escalate particularly in Japan
Investigators demotivated as not rewarded for their efforts
• Advances in scientific methodology ignored or rejected
• Sponsor companies maintain prejudices about difficulty of work in Asia
Path 2 – stagnation or reversal
Phase I – a routine after thoughtRoutine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US EUSolid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
Japan Phase -First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
Phase I – a routine after thoughtRoutine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US EUSolid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
Japan Phase -First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
EU/US dominated PK programme
Phase I – a routine after thoughtRoutine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US EUSolid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
Japan Phase -First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
EU/US dominated PK programme
No new data
Phase I – a routine after thoughtRoutine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US EUSolid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
Japan Phase -First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
EU/US dominated PK programme
No new dataCapability stagnates
Clinical trial activity – why invest more?
Companies continueto do minimum workfor approval
Japan Bridging StudyN = 200
Japan Bridging StudyN = 200
Korea Bridging Study
N = 200
Japan Bridging StudyN = 200
Korea Bridging Study
N = 200
China Bridging StudyN = 200
Japan Bridging StudyN = 200
Korea Bridging Study
N = 200
Taiwan Bridging StudyN = 200
China Bridging StudyN = 200
Japan Bridging StudyN = 200
Korea Bridging Study
N = 200
Philippine Bridging StudyN = 200
Taiwan Bridging StudyN = 200
China Bridging StudyN = 200
Japan Bridging StudyN = 200
Korea Bridging Study
N = 200
Philippine Bridging StudyN = 200
Taiwan Bridging StudyN = 200
China Bridging StudyN = 200
Thai Bridging StudyN = 200
Is this really the way ahead?
Japan Bridging StudyN = 200
Korea Bridging Study
N = 200
Philippine Bridging StudyN = 200
Taiwan Bridging StudyN = 200
China Bridging StudyN = 200
Thai Bridging StudyN = 200
Industry Academia MHLW
? ? ?
Industry Academia MHLW